Inflammation is the body's defense reaction to injuries such as those caused by mechanical damage, infection or antigenic stimulation. An inflammatory reaction may be expressed pathologically when inflammation is induced by an inappropriate stimulus such as an autoantigen, expressed in an exaggerated manner or persists well after the removal of the injurious agents.
Two important mediators of inflammation reaction are tumor necrosis factor (TNF) and interleukin-1 (IL-1). TNF neutralizer and IL-1 antagonist have been used to treat inflammation-dependent diseases.
Tumor necrosis factor-alpha (CNF alpha) and Tumor necrosis factor beta (INF-beta) are mammalian secreted proteins capable of inducing a wide variety of effects on a large number of cell types. The great similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as “TNF”.
TNF proteins initiate their biological effects on cells by binding to specific TNF receptor (TNFR) proteins expressed on the plasma membrane of a TNF-responsive cell. Two distinct forms of TNFR are known to exist: Type I TNFR (TNFRI), having a molecular weight of approximately 75 kilodaltons, and type II TNFR (TNFRII), having a molecular weight of approximately 55 kilodaltons. TNFRI and TNFRII each bind to both TNF alpha and TNF beta.
TNF antagonists, such as soluble TNFR and TNF binding proteins, bind to TNF and prevent TNF from binding to cell membrane bound TNF receptors. Such proteins were used to suppress biological activities caused by TNF.
The role of TNF in mediated inflammatory diseases has been well established. TNFRII have been proved to be safe and effective clinically for indications of TNF dependent disorders such as rheumatoid arthritis and psoriasis.
One of the most potent inflammatory cytokines is IL-1. IL-1 is manufactured by cells of the macrophage/monocyte lineage, and may be produced in two forms: IL-1 alpha and IL-1 beta. IL-1 proteins initiate their biological effects on cells by binding to specific IL-1 receptor (IL-1R), proteins expressed on the plasma membrane of an IL-1 responsive cell.
IL-1 receptor antagonist (IL-1ra) is a human protein that acts as a natural inhibitor of IL-1. IL-1ra binds to cell membrane bound IL-1 receptors and prevents IL-1 from binding to the same IL-1 receptors. This protein has been used to suppress biological activities caused by IL-1.
In theory, simultaneously neutralizing or blocking two important inflammatory mediators, such as TNF and IL-1, should have the best therapeutic value for treatment of inflammation dependent disorders. However, clinical trial of 242 patients and 24-weeks of concurrent use of a soluble TNFRII and non-glycosylated IL-1ra published by Immunex Inc and Amgen Inc did not increase the efficacy but lead to higher incidence of infection and neutrapenia than that of a soluble TNFRII and IL-1ra as monotherapy.